Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial

Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6–80.4, n = 40) and cohort 2 (34.3%; 95% CI, 17.0–51.8, n = 32). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 47 (65.3%) of 72 patients. Results of our predefined exploratory investigation of predictive biomarkers show: B cell markers are the most differentially expressed genes in the tumors of responders versus non-responders in cohort 1 and that tertiary lymphoid structure is associated with higher ORR; Angiogenesis gene expression signatures are strongly associated with ORR in cohort 2. Camrelizumab plus apatinib combination effectiveness is associated with high expression of PD-L1, VEGF Receptor 2 and B-cell-related genes signatures. Camrelizumab plus apatinib shows promising efficacy with a measurable safety profile in RM-NPC patients.

Sex was self-report and was not considered in study design. We confirm that the patients characteristics in the supplementary tables also include sex.
The manuscript used gender and age as the socially constructed or socially relevant categorization variables.The study aimed to examine the effect of gender and age on ORR and survival in different cohorts.Gender was self-reported by participants as male or female. Age was also self-reported as a continuous variable in years.There was no confounding variables in our analyses.The study did not onfounding variables, such as education, income, political ideology, and geographic region.
Patients with recurrent or metastatic nasopharyngeal carcinoma who had failed first-line platinum-based chemotherapy or were resistant to Anti-PD-1 monoclonal antibody were enrolled.The mean age was 45 years, and all patients had previously received at least first-line platinum-based treatment for RM NPC.
Participants were recruited from the Guangzhou area (China) via posters, emails, flyers, social media, and website advertisements. 72 participants were recruited into the trial after signing a written informed consent.Because all the participants were recruited from the Guangzhou area, they might not have been representative of the wider population. No other potential self-selection bias was present in this trial.
The trial was approved by the Research Ethics Board of Sun Yat-sen University Cancer Center and was done in accordance with the Declaration of Helsinki. All patients provided written informed consent.
N=72. Simon's optimal 2-stage design will be used for sample size calculation, with one-side test "=0.05 and power of test=0.8.
(1) Cohort 1: According to previous article, the ORR of RM-NPC treated with anti-PD-1 monoclonal antibody was about 25% after first-line platinum-based chemotherapy failed [14,[16][17]. Assuming that SHR-1210 plus apatinib lead to ORR achieved 50% for patients with RM-NPC who failed first-line platinum-based chemotherapy without prior use of anti-PD-1 monoclonal antibody. There were 9 patients enrolled in the first phase. If there were no more than 2 effective cases, the trial would be terminated. Otherwise, the second phase would be entered, and the number of patients enrolled in the second phase would be increased to 24. If there were no more than 9 effective cases (including the effective cases in the first phase), the trial would be terminated. Patients were enrolled for 1 year and followed up for 2 years. Considering the 10% loss to follow-up rate, 27 patients were enrolled in cohort 1.
(2) Cohort 2: Although the previously study found that the response rate of apatinib monotherapy in platinum-resistant NPC was about 30% [28], the objective response rate for PD-1 blockade resistant RM-NPC with apatinib monotherapy was still unkown. Therefore, we assumed that the objective response rate was 20 % with apatinib monotherapy in cohort 2, which was less than the objective response of 30% for PD-1 blockade-naive RM-NPC treated with apatinib monotherapy. The ORR of RM-NPC treated with apatinib was 20% after previous first-line platinum-based chemotherapy failed. Assuming that SHR-1210 plus apatinib lead to ORR achieved 45% for patients with RM-NPC who failed first-line platinum-based chemotherapy with prior use of anti-PD-1 monoclonal antibody. 10 patients were enrolled in the first phase. If there were no more than 2 effective cases were, the trial would be terminated. Otherwise, the second phase would be entered, and the number of patients enrolled in the second phase would be increased to 22. If there were no more than 7 effective cases (including the first phase), the trial would be terminated. Patients were enrolled for 1 year and followed up for 2 years. Considering the 10% loss to follow-up rate, 25 patients were enrolled in cohort 2. In order to make more patients will benefit from this trial and continue to evaluate stability and reliability of ORR and its 95% (CI) as the sample size increased, the principal investigator applied to the Research Ethics Committee of Sun Yat-sen University Cancer Center to amend the protocol and expanded the sample size, including 13 additional patients in the cohort 1 and 7 in the cohort 2.
(1) On January 31, 2021, the protocol was changed to include 13 more cohort 1 patients and 7 additional cohort 2 patients, for a total of 40 cohort 1 patients and 32 cohort 2 patients. Cohort 1(n=40): patients with RM-NPC who had failed first-line platinum-based chemotherapy and had not been treated with anti-PD-1 monoclonal antibody.
Reporting for specific materials, systems and methods We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. (2) Cohort 2(n=32): patients with RM-NPC who failed first-line platinum-based chemotherapy and continued to progress after treatment with anti-PD-1 monoclonal antibody.

None
Replication was not applicable as this was a clinical study with unique patient samples.

This was a single arm phase 2 study
This was a single arm, open label phase 2 study.